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Brain region dependent molecular signatures and myelin repair following chronic demyelination

Multiple sclerosis (MS) is the most prevalent demyelinating disease of the central nervous system, characterized by myelin destruction, axonal degeneration, and progressive loss of neurological functions. Remyelination is considered an axonal protection strategy and may enable functional recovery, b...

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Autores principales: Samtani, Grace, Kim, Sunja, Michaud, Danielle, Hillhouse, Andrew E., Szule, Joseph A., Konganti, Kranti, Li, Jianrong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10171432/
https://www.ncbi.nlm.nih.gov/pubmed/37180951
http://dx.doi.org/10.3389/fncel.2023.1169786
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author Samtani, Grace
Kim, Sunja
Michaud, Danielle
Hillhouse, Andrew E.
Szule, Joseph A.
Konganti, Kranti
Li, Jianrong
author_facet Samtani, Grace
Kim, Sunja
Michaud, Danielle
Hillhouse, Andrew E.
Szule, Joseph A.
Konganti, Kranti
Li, Jianrong
author_sort Samtani, Grace
collection PubMed
description Multiple sclerosis (MS) is the most prevalent demyelinating disease of the central nervous system, characterized by myelin destruction, axonal degeneration, and progressive loss of neurological functions. Remyelination is considered an axonal protection strategy and may enable functional recovery, but the mechanisms of myelin repair, especially after chronic demyelination, remain poorly understood. Here, we used the cuprizone demyelination mouse model to investigate spatiotemporal characteristics of acute and chronic de- and remyelination and motor functional recovery following chronic demyelination. Extensive remyelination occurred after both the acute and chronic insults, but with less robust glial responses and slower myelin recovery in the chronic phase. Axonal damage was found at the ultrastructural level in the chronically demyelinated corpus callosum and in remyelinated axons in the somatosensory cortex. Unexpectedly, we observed the development of functional motor deficits after chronic remyelination. RNA sequencing of isolated brain regions revealed significantly altered transcripts across the corpus callosum, cortex and hippocampus. Pathway analysis identified selective upregulation of extracellular matrix/collagen pathways and synaptic signaling in the chronically de/remyelinating white matter. Our study demonstrates regional differences of intrinsic reparative mechanisms after a chronic demyelinating insult and suggests a potential link between long-term motor function alterations and continued axonal damage during chronic remyelination. Moreover, the transcriptome dataset of three brain regions and over an extended de/remyelination period provides a valuable platform for a better understanding of the mechanisms of myelin repair as well as the identification of potential targets for effective remyelination and neuroprotection for progressive MS.
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spelling pubmed-101714322023-05-11 Brain region dependent molecular signatures and myelin repair following chronic demyelination Samtani, Grace Kim, Sunja Michaud, Danielle Hillhouse, Andrew E. Szule, Joseph A. Konganti, Kranti Li, Jianrong Front Cell Neurosci Neuroscience Multiple sclerosis (MS) is the most prevalent demyelinating disease of the central nervous system, characterized by myelin destruction, axonal degeneration, and progressive loss of neurological functions. Remyelination is considered an axonal protection strategy and may enable functional recovery, but the mechanisms of myelin repair, especially after chronic demyelination, remain poorly understood. Here, we used the cuprizone demyelination mouse model to investigate spatiotemporal characteristics of acute and chronic de- and remyelination and motor functional recovery following chronic demyelination. Extensive remyelination occurred after both the acute and chronic insults, but with less robust glial responses and slower myelin recovery in the chronic phase. Axonal damage was found at the ultrastructural level in the chronically demyelinated corpus callosum and in remyelinated axons in the somatosensory cortex. Unexpectedly, we observed the development of functional motor deficits after chronic remyelination. RNA sequencing of isolated brain regions revealed significantly altered transcripts across the corpus callosum, cortex and hippocampus. Pathway analysis identified selective upregulation of extracellular matrix/collagen pathways and synaptic signaling in the chronically de/remyelinating white matter. Our study demonstrates regional differences of intrinsic reparative mechanisms after a chronic demyelinating insult and suggests a potential link between long-term motor function alterations and continued axonal damage during chronic remyelination. Moreover, the transcriptome dataset of three brain regions and over an extended de/remyelination period provides a valuable platform for a better understanding of the mechanisms of myelin repair as well as the identification of potential targets for effective remyelination and neuroprotection for progressive MS. Frontiers Media S.A. 2023-04-26 /pmc/articles/PMC10171432/ /pubmed/37180951 http://dx.doi.org/10.3389/fncel.2023.1169786 Text en Copyright © 2023 Samtani, Kim, Michaud, Hillhouse, Szule, Konganti and Li. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Samtani, Grace
Kim, Sunja
Michaud, Danielle
Hillhouse, Andrew E.
Szule, Joseph A.
Konganti, Kranti
Li, Jianrong
Brain region dependent molecular signatures and myelin repair following chronic demyelination
title Brain region dependent molecular signatures and myelin repair following chronic demyelination
title_full Brain region dependent molecular signatures and myelin repair following chronic demyelination
title_fullStr Brain region dependent molecular signatures and myelin repair following chronic demyelination
title_full_unstemmed Brain region dependent molecular signatures and myelin repair following chronic demyelination
title_short Brain region dependent molecular signatures and myelin repair following chronic demyelination
title_sort brain region dependent molecular signatures and myelin repair following chronic demyelination
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10171432/
https://www.ncbi.nlm.nih.gov/pubmed/37180951
http://dx.doi.org/10.3389/fncel.2023.1169786
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